This project proposes to test the hypothesis that apoE and cholesterol modify Abeta deposition in an isoform-dependent fashion with the apoE4 allele acting in a dominant mode. Rare mutations in amyloid precursor protein (APP) are responsible for some cases of early onset autosomal dominant Alzheimer's disease (AD). Isoform differences at the AD susceptibility gene apolipoprotein (apo) E locus affect age of onset for late on-set AD, and may influence from 15-50% of all cases. In humans, there are three major apoE isoforms designated apoE2, E3, and E4 that differ by a single amino acid. ApoE functions to maintain cholesterol and fat homeostasis. ApoE isoforms also interact either directly or indirectly with APP to modulate the extent of Abeta deposition associated with one dimension of AD pathology. Current human studies suggest that high cholesterol increases the risk of AD. Animal studies reveal significant effects of cholesterol on APP and apoE metabolism in the brain, and on Abeta deposition, and suggest a major environmental (i.e. dietary fat and cholesterol) may modify AD pathology. We have transgenic animal models to test this hypothesis, human apoE targeted replacement mice, human apoE transgenic mice and the human APPV717F transgenic mouse. ApoE isoform-specific promoter effects on brain apoE levels will be measured under basal and high cholesterol conditions. AD-related pathology will be examined by crossing the apoE targeted replacement animals to mice bearing a human APP mutation using Abeta deposition and APP metabolism as endpoints. Finally, the ability to create animal models of the common human heterozygote, APOE3/4, will allow testing for dominant-positive or dominant-negative effects of human apoE isoforms. Modeling dietary factors that may modulate APP and apoE will advance the understanding of environmental and genetic interactions that influence the onset and progression of AD.